IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-33421-7.html
   My bibliography  Save this article

Structural mechanism of SGLT1 inhibitors

Author

Listed:
  • Yange Niu

    (Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University)

  • Wenhao Cui

    (Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University
    Shandong University)

  • Rui Liu

    (Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University)

  • Sanshan Wang

    (Peking University
    Synthetic and Functional Biomolecules Center)

  • Han Ke

    (Peking University
    Synthetic and Functional Biomolecules Center)

  • Xiaoguang Lei

    (Peking University
    Synthetic and Functional Biomolecules Center)

  • Lei Chen

    (Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine
    Peking University
    Peking University)

Abstract

Sodium glucose co-transporters (SGLT) harness the electrochemical gradient of sodium to drive the uphill transport of glucose across the plasma membrane. Human SGLT1 (hSGLT1) plays a key role in sugar uptake from food and its inhibitors show promise in the treatment of several diseases. However, the inhibition mechanism for hSGLT1 remains elusive. Here, we present the cryo-EM structure of the hSGLT1-MAP17 hetero-dimeric complex in the presence of the high-affinity inhibitor LX2761. LX2761 locks the transporter in an outward-open conformation by wedging inside the substrate-binding site and the extracellular vestibule of hSGLT1. LX2761 blocks the putative water permeation pathway of hSGLT1. The structure also uncovers the conformational changes of hSGLT1 during transitions from outward-open to inward-open states.

Suggested Citation

  • Yange Niu & Wenhao Cui & Rui Liu & Sanshan Wang & Han Ke & Xiaoguang Lei & Lei Chen, 2022. "Structural mechanism of SGLT1 inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33421-7
    DOI: 10.1038/s41467-022-33421-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-33421-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-33421-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Weixiao Y. Wahlgren & Elin Dunevall & Rachel A. North & Aviv Paz & Mariafrancesca Scalise & Paola Bisignano & Johan Bengtsson-Palme & Parveen Goyal & Elin Claesson & Rhawnie Caing-Carlsson & Rebecka A, 2018. "Substrate-bound outward-open structure of a Na+-coupled sialic acid symporter reveals a new Na+ site," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    2. Chengcheng Guan & Yange Niu & Si-Cong Chen & Yunlu Kang & Jing-Xiang Wu & Koji Nishi & Catherine C. Y. Chang & Ta-Yuan Chang & Tuoping Luo & Lei Chen, 2020. "Structural insights into the inhibition mechanism of human sterol O-acyltransferase 1 by a competitive inhibitor," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    3. Paola Bisignano & Chiara Ghezzi & Hyunil Jo & Nicholas F. Polizzi & Thorsten Althoff & Chakrapani Kalyanaraman & Rosmarie Friemann & Matthew P. Jacobson & Ernest M. Wright & Michael Grabe, 2018. "Inhibitor binding mode and allosteric regulation of Na+-glucose symporters," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Wenhao Cui & Yange Niu & Zejian Sun & Rui Liu & Lei Chen, 2023. "Structures of human SGLT in the occluded state reveal conformational changes during sugar transport," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Wenhao Cui & Yange Niu & Zejian Sun & Rui Liu & Lei Chen, 2023. "Structures of human SGLT in the occluded state reveal conformational changes during sugar transport," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Farha Khan & Matthias Elgeti & Samuel Grandfield & Aviv Paz & Fiona B. Naughton & Frank V. Marcoline & Thorsten Althoff & Natalia Ermolova & Ernest M. Wright & Wayne L. Hubbell & Michael Grabe & Jeff , 2023. "Membrane potential accelerates sugar uptake by stabilizing the outward facing conformation of the Na/glucose symporter vSGLT," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Qing Zhang & Deqiang Yao & Bing Rao & Liyan Jian & Yang Chen & Kexin Hu & Ying Xia & Shaobai Li & Yafeng Shen & An Qin & Jie Zhao & Lu Zhou & Ming Lei & Xian-Cheng Jiang & Yu Cao, 2021. "The structural basis for the phospholipid remodeling by lysophosphatidylcholine acyltransferase 3," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    4. August George & Paola Bisignano & John M Rosenberg & Michael Grabe & Daniel M Zuckerman, 2020. "A systems-biology approach to molecular machines: Exploration of alternative transporter mechanisms," PLOS Computational Biology, Public Library of Science, vol. 16(7), pages 1-21, July.
    5. Kun Wang & Chia-Wei Lee & Xuewu Sui & Siyoung Kim & Shuhui Wang & Aidan B. Higgs & Aaron J. Baublis & Gregory A. Voth & Maofu Liao & Tobias C. Walther & Robert V. Farese, 2023. "The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Xuewu Sui & Kun Wang & Kangkang Song & Chen Xu & Jiunn Song & Chia-Wei Lee & Maofu Liao & Robert V. Farese & Tobias C. Walther, 2023. "Mechanism of action for small-molecule inhibitors of triacylglycerol synthesis," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    7. Martin F. Peter & Jan A. Ruland & Peer Depping & Niels Schneberger & Emmanuele Severi & Jonas Moecking & Karl Gatterdam & Sarah Tindall & Alexandre Durand & Veronika Heinz & Jan Peter Siebrasse & Paul, 2022. "Structural and mechanistic analysis of a tripartite ATP-independent periplasmic TRAP transporter," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. James S. Davies & Michael J. Currie & Rachel A. North & Mariafrancesca Scalise & Joshua D. Wright & Jack M. Copping & Daniela M. Remus & Ashutosh Gulati & Dustin R. Morado & Sam A. Jamieson & Michael , 2023. "Structure and mechanism of a tripartite ATP-independent periplasmic TRAP transporter," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33421-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.